The human macrophage migration inhibitory factor (MIF, also known as GIF, GLIF, Glycosylation-inhibiting factor, L-dopachrome isomerase or L-dopachrome tautomerase) is described in David, J. (1966) Proc. Natl. Acad. Sci. U.S.A. 56: 72-77 and Bloom, B. R & Bennett, B. (1966) Science 153, 80-82 and was identified as a central regulator of innate immunity and inflammatory responses (Calandra, T. (2003) Nature Reviews Immunology Vol. 03; 791-800).
The MIF gene is located on chromosome 22 of the human genome and encodes a 115 amino acids long non-glycosylated protein of 12.5 kDa which forms a homotrimer (Sun, H. W., (1996) Proc. Natl. Acad. Sci. U.S.A. 93: 5191-5196).
MIF is constitutively expressed in virtually all cell types. During inflammation macrophages, T cells and the pituitary gland are the predominant sources of MIF (Bernhagen, J. (1993) Nature 365:756-759; Calandra, T. (1994) J. Exp. Med. 179:1895-1902). Secreted MIF interacts with its receptors CD74, CXCR2 and CXCR4 which are expressed e.g. on macrophages and T-cells and induces release of pro-inflammatory cytokines (e.g. TNFα, IL-1β, IL-6 IL-8, IFNγ, IL-2), cell invasion and cell migration (Leng L. (2003) J. Exp. Med. 197:1467-1476; Bernhagen, J. (2007) Nature Medicine 13: 587-596).
MIF as a pro-inflammatory mediator was identified to be involved and overexpressed in several inflammatory diseases and also polymorphisms of MIF were shown to correlate with the severity of autoinflammatory diseases (Hoi, A. J. (2007) Inflammation & Allergy—Drug Targets, 6: 183-190; Baugh, J. A. (2002) Genes Immun. 3: 170-176).
In addition, further studies describe that MIF negatively regulates p53-mediated apoptosis and cell arrest and thereby provide a link between MIF, cell growth and tumorigenesis (Calandra, T. (2003) Nature Reviews Immunology 03; 791-800; Hudson, J. D. (1999) J. Exp. Med. 190:1375-1382).
Upon identifying MIF as a key player not only in the pathogenesis of a range of immune-mediated inflammatory diseases but also in cancer and further indications, MIF became a promising therapeutic target to be antagonized with compounds like e.g. small molecules or monoclonal antibodies.
Antibodies specific for MIF are disclosed e.g. in WO1994/026307 (The Picower Institute For Medical Research), U.S. Ser. No. 08/471,705 which are all incorporated by reference in its entirety; WO1998/017314 (The Picower Institute For Medical Research), WO2001/038566 (Fraunhofer-Gesellschaft Zur Förderung Der Angewandten Forschung E.V.), U.S. Ser. No. 12/234,407 which are all incorporated by reference in its entirety; WO2002/036774 (Fraunhofer-Gesellschaft Zur Förderung Der Angewandten Forschung E.V.), WO2009/086920 (Baxter International Inc., Baxter Healthcare S.A., Dyax Corporation), U.S. Ser. Nos. 12/346,309 and 12/767,635 which are all incorporated by reference in its entirety; WO2009/117710 (Carolus Therapeutics Inc.), WO2009/117706 (Carolus Therapeutics Inc.), U.S. Ser. No. 12/918,968 which are all incorporated by reference in its entirety; WO2005/020919 (Cytokine Pharmasciences, Inc.), WO2005/094329 (Cytokine Pharmasciences, Inc.), U.S. Ser. No. 10/927,494 which are all incorporated by reference in its entirety; WO2005/094338A2 (North Shore-Long Island Jewish Research Institute), U.S. Ser. No. 10/594,641 which are all incorporated by reference in its entirety.
Notably, based on the finding that MIF is enzymatically active as a tautomerase and converts D-Dopachrome into 5,6-dihydroxyindole-2-carboxylic acid a homolog of MIF was identified which shares the tautomerase activity producing a similar but not identical product, 5,6-dihydroxyindole. The MIF homolog, which is called D-dopachrome tautomerase (D-DT), shows low sequence homology of 47% to MIF (FIG. 1). In 2008 it was shown that D-DT and MIF share specific functionalities and promote both the expression and secretion of angiogenic growth factors, e.g. CXCL8 and VEGF, from lung adenocarcinoma cells (Coleman, A. M. (2008) J. of Immunology 118(4):2330-2337).
Accordingly, therapies that interfere with MIF and D-DT mediated signaling are needed.